PURPOSE OF REVIEW: Analyses of the host transcriptional response to infection has proved to be an alternative diagnostic strategy to standard direct pathogen detection. This review summarizes the value of applying blood and mucosal transcriptome analyses for the diagnosis and management of children with viral and bacterial infections. RECENT FINDINGS: Over the years, studies have validated the concept that RNA transcriptional profiles derived from children with infectious diseases carry a pathogen-specific biosignature that can be qualitatively and quantitively measured. These biosignatures can be translated into a biologically meaningful context to improve patient diagnosis, as seen in children with tuberculosis, rhinovirus infections, febrile infants and children with pneumonia; understand disease pathogenesis (i.e. congenital CMV) and objectively classify patients according to clinical severity (i.e. respiratory syncytial virus). SUMMARY: The global assessment of host RNA transcriptional immune responses has improved our understanding of the host-pathogen interactions in the clinical setting. It has shown the potential to be used in clinical situations wherein our current diagnostic tools are inadequate, guiding the diagnosis and classification of children with infectious diseases.